Cycle 1 and further cycles

Ramucirumab is TGA approved but not PBS reimbursed for this indication

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1

Loratadine

10 mg (PO)

60 minutes before treatment

Ramucirumab

8 mg/kg (IV infusion)

in a final volume of 250 mL sodium chloride 0.9% over approximately 60 minutes (maximum infusion rate 25 mg/min)

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and further cycles

Day 1

Loratadine

10 mg (PO)

60 minutes before treatment

Ramucirumab

8 mg/kg (IV infusion)

in a final volume of 250 mL sodium chloride 0.9% over approximately 60 minutes (maximum infusion rate 25 mg/min)

Indication:

second line therapy for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma in patients with disease progression after prior platinum or fluoropyrimidine chemotherapy, given as monotherapy when treatment in combination with paclitaxel is not appropriate

Hypersensitivity reactions, including acute infusion related reaction (IRR) may occur. Hypersensitivity risk is greatest during the first two cycles of ramucirumab.

Premedication

Premedication with a H1 antagonist is recommended prior to administration of ramucirumab.

Please refer to the treatment schedule for a suggested premedication regimen. This may be substituted to reflect institutional policy.

The product information for ramucirumab recommends:

If a patient experiences a grade 1 or 2 infusion related reaction (IRR), premedication must be given for all subsequent infusions.

If a patient experiences a second grade 1 or 2 IRR despite premedication with a H1 antagonist, administer dexamethasone or equivalent; then, for subsequent infusions, premedicate with the following or equivalent medications: promethazine (intravenously), paracetamol and dexamethasone.

Emetogenicity MINIMAL

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.

Gastrointestinal (GI) perforation has been reported in patients treated with ramucirumab. Use with caution in patients at risk of GI perforation (e.g. prior surgery or radiotherapy).

Patients should be monitored for signs and symptoms of GI perforation and ramucirumab should be permanently discontinued if GI perforation occurs.

Haemorrhage

Patients treated with ramucirumab have an increased risk of haemorrhage, especially severe gastrointestinal haemorrhage. Ramucirumab should be used with caution in patients at risk of bleeding (e.g. patients with conditions predisposing to bleeding, and patients taking concurrent anticoagulant or antiplatelet medications).

Ramucirumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding.

Hypertension

Ramucirumab may increase the risk of hypertension.

Pre-existing hypertension should be adequately controlled prior to commencing ramucirumab.

Monitor blood pressure regularly throughout treatment. Withhold ramucirumab in patients who develop hypertension until it is adequately controlled. Commence or adjust antihypertensive medication as clinically indicated.

Patients may be at increased risk of developing severe proteinuria and/or nephrotic syndrome when treated with ramucirumab. Baseline urinalysis for proteinuria is recommended prior to commencement of therapy, and throughout treatment as clinically indicated. Treatment interruption may be required if proteinuria is significant. Ramucirumab should be discontinued in the event of nephrotic syndrome.

Ramucirumab has not been studied in patients with serious or non-healing wounds. There is potential for impaired wound healing based on the mechanism of action.

Ramucirumab treatment should be withheld for at least 4 weeks prior to scheduled surgery and recommenced when wounds have adequately healed. If wound healing complications occur, withhold ramucirumab until the wound is fully healed.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Ramucirumab should be discontinued in patients who develop reversible posterior leukoencephalopathy syndrome (RPLS). The risk of reinitiating ramucirumab therapy in patients previously experiencing RPLS is not known.

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Studies to evaluate the effect of ramucirumab on human fertility have not been performed. Female fertility is likely to be compromised during treatment with ramucirumab based on studies in animals.

Ramucirumab is not recommended during pregnancy. Based on it's mechanism of action it is likely that ramucirumab can cause fetal harm when given to pregnant women. It is important that females of reproductive potential use effective contraception whilst on therapy and for at least 3 months after the last dose of therapy.

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. For more information see dosing considerations & disclaimer.

Renal impairment

Mild or moderate

No dose reductions are recommended

Severe

No safety data available

Hepatic impairment

Hepatic dysfunction

Mild or moderate

There have been no formal studies with ramucirumab in patients with hepatic impairment.
No dose reductions are recommended.

Severe

There have been no formal studies with ramucirumab in patients with hepatic impairment.
No dose reductions are recommended.
Use ramuciumab with caution in patients with severe liver cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal syndrome. Use only if potential benefits outweigh the potential risk of progressive hepatic failure

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.

Digoxin

Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin

Monitor digoxin serum levels; adjust digoxin dosage as appropriate

Antiepileptics

Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity

Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy

Diminished response to vaccines and increased risk of infection with live vaccines

Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Discharge information

Patient information

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)

Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Dull ache, cramping or sharp pains are common with some antineoplastic drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.

Arterial thromboembolic events, including myocardial infarction, cardiac arrest, cerebrovascular accident and cerebral ischaemia can occur. Patients should be carefully assessed for risk factors, and consideration given for antithrombotic prophylaxis in high risk patients.

The evidence supporting this protocol is provided by a phase III, multicentre, international, randomised trial (REGARD) involving 355 patients comparing ramucirumab monotherapy with placebo in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma following progression on platinum or fluoropyrimidine-based chemotherapy.r

Between Oct 6, 2009 and Jan 26, 2012, 238 patients were randomised to receive ramucirumab 8 mg/kg and 117 patients were randomised to receive a placebo. Both ramucirumab and placebo were administered by intravenous infusion every 14 days until disease progression or unacceptable toxicity.r

The primary end point was overall survival and secondary end points were progression-free survival, objective response rate, duration of response, quality of life, safety and ramucirumab immunogenicity.r

Efficacy

Ramucirumab compared to placebo demonstrated a low magnitude benefit in terms of overall survival (grade 1 out of 5, where grades 4 and 5 represent substantial improvement, according to the European Society for Medical Oncology Magnitude of Clinical benefit Scale [ESMO-MCBS] v1.1). r

At the time of data cutoff, the median overall survival (OS) was 5.2 months in the ramucirumab group vs 3.8 months in the placebo group (HR=0.776; CI 95% 0.603 to 0.998 ; p=0.047). The estimated rates of 6 month overall survival were 41.8% (95% CI 35.4 to 48.1) in the ramucirumab group and 31.8% (23.3 to 40.2) in the placebo group; rates at 12 months were 17.6% (11.8 to 24.3) vs 11.8% (6.0 to19.7) respectively.r

Quality of life data was recorded but was not reliable due to a low proportion of patients reporting. There was a trend to improved quality of life of ramucirumab however this was not statistically significant (p=0.23).r

Toxicity

Ramucirumab was well tolerated in the REGARD trial. There were similar rates for most adverse events between the ramucirumab and placebo groups.r

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Version 1

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au